Amyotrophic lateral sclerosis (ALS), a disease in which premature loss of upper and lower motor neurons leads to fatal paralysis, is increasingly recognized to have clinical, genetic and pathological overlap with frontotemporal lobar degeneration (FTLD), a neurodegenerative disorder characterized by behavioral and language dysfunction. In 2006, TAR DNA-binding protein 43 (TDP-43) was identified as the major component of ubiquitinated cytoplasmic inclusions observed in both ALS and FTLD patients and dominant mutations in the gene TARDBP were subsequently identified as a primary cause of ALS. ALS is the most common motor neuron disease in adults and FTLD the most common dementia under the age of 60. Nevertheless, there are no effective therapies for these neurodegenerative disorders and management focuses on treating the symptoms and providing palliative care in order to improve the quality of life of these patients. Immunotherapies against neurodegenerative diseases are still at their early stages of development. Yet, we believe that they hold tremendous potential due to their direct impact on the underlying disease biology and their potential to delay disease progression. Naturally occurring human monoclonal antibodies represent novel therapeutic molecules for neurologic disorders including ALS. It is postulated that human autoantibodies targeting misfolded pathogenic proteins, such as TDP-43, serve as surveillance molecules to eliminate toxic aggregates before they can elicit a deleterious response. Such antibodies might neutralize the activity of oligomers and/or facilitate clearance of deposited aggregates via microglia uptake. Chimeric or humanized antibodies can elicit an adverse immune response, resulting in severe side-effects, even death, and reduced efficacy of the therapeutic antibody due to neutralization by the human immune system. Autoantibodies retrieved from individuals with no debilitating conditions have a higher safety profile, as the antibody has proven tolerability in the human body. Combined with the outstanding affinity maturation typical of the human immune system, those antibodies are likely to offer a therapeutic window superior to antibodies of non-human origin. A bottleneck in the development of effective therapies against ALS and FTLD is the lack of models with pathological features faithfully resembling those present in patient brains. Our recent work has established new cellular models of TDP-43 aggregation, via the introduction of pathological forms extracted directly from patient brains, leading to accumulation and propagation of pathology in cell lines and human neurons via a mechanism mimicking the molecular events leading to disease progression. In this project, we will capitalize on these tools to develop TDP-43 immunotherapy. Our strategy is to identify patients with naturally occurring protective autoantibodies targeting pathological forms of TDP-43 and to proceed with their respective cloning, characterization and development for therapeutic use in ALS and FTLD.